Fluoro-curcuminoids and curcuminoid-BF2adducts: Synthesis, X-ray structures, bioassay, and computational/docking study

Abstract

A series of α-carbonyl fluorinated curcuminoids were synthesized by direct mono- and difluorination with Selectfluor (F-TEDA-BF4) at r.t. without using a base or additive. Ring fluorinated/trifluoromethylated curcuminoid-BF2adducts were synthesized by reaction of the corresponding benzaldehydes with acetylacetone-BF2. Decomplexation of CUR-BF2adducts under microwave irradiation gave the corresponding curcuminoids. Multinuclear NMR and X-ray analysis confirm that curcuminoids bearing fluorines or trifluoromethyl groups in the aryl rings as well as those that are monofluorinated at the active methylene position all exist as enol tautomers. The α,α-difluorination brings about significant conformational change as these curcuminoids become fixed in the 1,3-diketone configuration. The X-ray structures of CUR-BF2complexes are consistent with the formation of symmetrical adducts with equal B[sbnd]O bond distances. The anti-proliferative activity of these compounds were tested by in-vitro bioassay against several different cancer cell lines. The corresponding CUR-BF2adducts exhibited exceptionally high activities at micromolar and in some cases nanomolar concentrations that greatly surpass the activity of parent curcumin. Computational docking calculations were performed to gauge binding energies of these compounds in HER2 protein, and in 20S proteasome, for comparison with the bioassay-derived activity data.